Optically-active derivatives of (R) 5-pentylamino-5-oxopentanoic acid with antagonistic activity towards cholecystokinin and a method for their preparation

ABSTRACT

There are described optically active derivatives of (R) 5-pentylamino-5-oxopentanoic acid and their pharmaceutically acceptable salts, having antagonistic activity towards cholecystokinin, and with the formula: ##STR1## in which R 1  is selected from the groups 2-naphthyl, 3,4-dichlorophenyl and 3,4-dimethylphenyl and R 2  is a pentyl group or an alkoxyalkyl group with 4 carbon atoms, and in which the substituents on the central chiral group (marked with an asterisk in Formula (I)), have the R (rectus) conformation.

This is a divisional of U.S. Appln. No. 08/131,573 filed Oct. 4, 1993,U.S. Pat. No. 5,391,574 in turn a continuation of U.S. Appln. No.07/902,561 filed Jun. 22, 1992, abandoned, which is a continuation ofU.S. Appln. No. 07/425,148 filed Oct. 23, 1989, abandoned, in turn acontinuation of U.S. application No. 07/152,724, filed Feb. 5, 1988,abandoned.

DESCRIPTION

The subjects of the present invention are original derivatives of (R)5-pentylamino-5-oxopentanoic acid, which may be represented by thegeneral formula indicated below: ##STR2## in which R₁ is selected fromthe groups 2-naphthyl, 3,4-dichlorophenyl and 3,4-dimethylphenyl and R₂is a pentyl group or an alkoxyalky group with 4 carbon atoms, and inwhich the substituents on the central chiral group (marked with anaserisk in Formula (I)) have the R (rectus) conformation.

R₂ is preferably selected from the group consisting of the pentyl,2-ethoxyethyl and 3-methoxypropyl groups.

The compounds which are the subject of the present invention display apowerful antagonistic activity towards cholecystokinin (CCK). Thecompounds according to the invention may thus be used to advantage inthe treatment of various illnesses in man, such as illnesses of thedigestive system, as for example, in the treatment of colitis, ofbiliary diskinesia and pancreatitis.

On the basis of their pharmacological characteristics, their use mayalso be envisaged in the treatment of mental disorders attributable todeficiencies in the physiological neuron levels of CCK or of otherrelated bioactive polypeptides and also in the treatment of anorexia.

The compounds which are the subject of this invention, as alreadymentioned, have a powerful anti-CCK activity in various experimentalsituations, both in vivo and in vitro.

Thus, in nanomolar concentrations, they inhibit the binding of markedcholecystokinin to the cell membranes of the gallbladder of an ox, atissue which is considered to be a target organ for the physiologicalaction of cholecystokinin.

Moreover, these compounds are also very active in vivo. For example,they inhibit, in a dose-dependent manner, some even with a dose of lessthan 0.1 mg/kg, the contraction and emptying of the gallbladder inducedby egg yolk, which is an inducer for the endogenous release of CCK. Theyalso encourage emptying of the stomach by inhibiting the piloriccontraction caused by CCK.

Moreover their protective action is particularly powerful againstexperimental pancreatitis, for example, against pancreatitis induced bysodium taurocholate.

Pharmaceutical forms of the compounds which are the subject of theinvention may be prepared by conventional techniques, for example aspills, capsules, suspensions, solutions and suppositories and may beadministered orally, parenterally or rectally.

The active ingredient is administered to the patient typically in aratio of 0.005 to 5 mg/kg of body weight per dose. For parenteraladministration, it is preferable to use a water-soluble salt of thesubject compounds, such as the sodium salt or another salt which isnon-toxic and pharmaceutically acceptable. Substances commonly used inthe pharmaceutical industry as excipients, binders, flavourings,dispersants, colouring agents, humectants, etc. may be used as inactiveingredients.

These derivatives of 5-pentylamino-5-oxopentanoic acid form part of aclass of compounds which is the subject of earlier Patents of theApplicant which describe a method for producing the subject compounds,but in the racemic form (R,S) starting from L-glutamic acid.

The present invention arises from the following two considerations:

A) the anti-cholecystokinin activity of the compounds which are thesubject of the patents mentioned above is due to the enantiomeric Rforms, which correspond to the starting D-glutamic acid. This fact isquite surprising considering the fact that the natural aminoacids whichare biologically active all belong to the L series.

B) The method described previously does not enable configuration to beretained; that is, whether L-glutamic acid or D-glutamic acid was usedas the starting material, (R,S) derivatives of pentanoic acid wereproduced.

Another object of the present invention is, therefore, to provide amethod which ensures that configuration is retained in successivetransformations and which therefore enables the5-pentylamino-5-oxopentanoic derivatives to be obtained from D-glutamicacid in the optically active R (rectus) form which is thepharmacoloigcally-active enantiomeric form.

The method for the preparation of the derivatives which are the subjectof the present invention, is characterised in that it comprises thesteps of:

a) reacting the gamma-benzyl ester of N-carbobenzoxy-D-glutamic acidwith an amine of formula ##STR3## in which R₂ has the meaning attributedto it above, by the mixed anhydride method in an inert anhydrous solventat a temperature of between -15° and +15° to give the compounds offormula (III); (see reaction scheme below)

b) debenzylating and decarbobenzoxylating the compound of formula (III)dissolved in an inert solvent by reacting it with hydrogen at ambienttemperature and atmospheric pressure in the presence of a catalyticallyeffective quantity of a hydrogenation catalyst to obtain the derivativesof formula (II) (see scheme below)

c) reacting the derivatives of formula (II) under Schotten-Baumanconditions with an equivalent quantity of an acyl chloride of formula R₁-COCl, in which R₁ has the meaning attributed to it above, at atemperature of from 0° to 15° C. and recovering the (R)4-acylamino-5-pentylamino-5-oxopentanoic derivatives of formula (I) fromthe reaction mass.

The series of steps of the method according to the invention isillustrated as a whole in the following reaction scheme: ##STR4##

The amidation step (a) is carried out preferably at a temperature ofbetween -15° and -10° C. over a period of from 1 to 24 hours, preferablyfor 6 hours with the reagents in a stoichiometric ratio. The preferredsolvent for the reaction is selected from chloroform, dioxan andtetrahydrofuran.

The hydrogenation step (b) is preferably carried out in the presence ofpalladium supported on carbon, with between 0.02 and 0.001 atoms ofpalladium per mole of compound (III), in a methanolic solution, atambient temperature and pressure, in a stream of hydrogen for a periodof from 1 to 12 hours, preferably 3 hours. The acylation step (c) ispreferably carried out at a temperature of approximately 5° C. for aperiod of from 1 to 24 hours, preferably 12 hours.

The following examples are given in order better to illustrate theinvention.

EXAMPLE 1

Preparation of the benzyl ester of (R)4-carbobenzoxyamino-5-(di-n-pentylamino)-5-oxopentanoic acid (compound 1of Table 1). 37.1 g(0.1 moles) of the gamma-benzyl ester ofN-carbobenzoxy-D-glutamic acid are dissolved in 250 ml of anhydroustetrahydrofuran, the solution is cooled to -10° C. and 10.1 g (0.1moles) of triethylamine are added with agitation; 10.8 g (0.1 moles) ofethyl chlorocarbonate are then added, still at -10° C. The temperatureis maintained at -10° C. for 20 minutes and then 15.7 g (0.1 moles) ofdi-pentylamine are added. Agitation is continued for a further 6 hoursand the temperature rises to ambient temperature; it is dried and theresidue is taken up in ethyl acetate.

It is washed with 2N HCl, sodium bicarbonate and finally with water;then it is dried over anhydrous Na₂ SO₄. By concentration to smallvolume, an oily residue is obtained (mw 510.6), which does notcrystallise, with a chromatographic purity of more than 95%.

TLC: Rf 0.81 (chloroform-ethyl acetate 7/3 V/V).

46.5 g obtained. Yield 91%.

All the compounds of formula III are crystallised by the same method(see scheme above). The compounds obtained are shown with someidentifying characteristics as well as the yields obtained in Table 1below.

EXAMPLE 2

Preparation of (R) 4-amino-5-(di-n-pentylamino)-5-oxopentanoic acid(compound 4 of table 2).

51.1 g (0.1 moles) of the benzyl ester of (R)4-carbobenzoxyamino)-5-(di-n-pentylamino)-5-oxopentanoic acid aredissolved in 300 ml of methanol, with the addition of 1 g of carbonpalladiate at 10% and hydrogenated at ambient temperature with a streamof hydrogen for 3 hours. The catalyst is filtered off and the methanolis distilled under vacuum. An oily residue is obtained (mw 286.4) whichdoes not crystallise, with a chromatographic purity of more than 95%.

TLC: Rf 0.75 (n-Butanol-acetic acid-H₂ O 5/2/2 V/V/V).

All the compounds of formula II are synthesised by the same method (seescheme).

The compounds obtained are shown with some identifying characteristicsas well as the yields obtained below.

EXAMPLE 3

Preparation of (R)4-(2-naphthylamino)-5-(di-n-pentylamino)-5-oxopentanoic acid, (Compound7 of Table 3).

28.6 g (0.1 moles) of (R) 4-amino-5- (di-n-pentylamino)-5-oxopentanoicacid are suspended in 300 ml of water and then dissolved with agitationby the addition of 10.6 g (0.1 moles) of sodium carbonate. Then 19.1 g(0.1 moles) of 2-naphthoyl chloride are added in 1 hour at 0° C. withagitation.

The mixture is left for 12 hours to react.

It is made acid to Congo red with dilute HCl and the precipitate thusformed, is filtered off. It is crystallised from H₂ O-ethanol (2/1).

M.P.69°-72° C. TLC (iso-amyl alcohol-acetone-H₂ O: 5/2/1): Rf 0.83 37 gobtained (mw 440.6) Yield 84%. Rotary power: [alpha]D²⁰ =+11.0 (c=2.5%in 95% ethanol).

All the compounds of formula I (see scheme) are synthesised by the samemethod.

Some examples of these compounds with some identifying characteristicsas well as the yields obtained are given by way of example in Table 3below.

In order to compare the anti-CCK activity of the derivatives of (R)5-pentylamino-5-oxopentanoic acid with the corresponding (S) seriesenantiomers, some of these derivatives were synthesised by the methoddescribed above but, in this case, starting from the gamma-benzylesterof N-carbobenzoxy-L-glutamic acid.

Table 4 shows some of the (S)4-acylamino-5-(di-n-pentylamino)-5-oxopentanoic derivatives thusobtained and used for the pharmacological comparisons with some of theiridentifying characteristics.

                  TABLE 1                                                         ______________________________________                                        derivatives having the formula:                                                ##STR5##                                                                     Compound  R.sub.2       Rf*    Formula                                        ______________________________________                                        1         pentyl        0.71   C.sub.30 H.sub.42 N.sub.2 O.sub.5              2         3-methoxypropyl                                                                             0.22   C.sub.29 H.sub.40 N.sub.2 O.sub.6              3         2-ethoxyethyl 0.28   C.sub.29 H.sub.40 N.sub.2 O.sub.6              ______________________________________                                         *eluents: chloroform/ethyl acetate 9/1V/V                                

                  TABLE 2                                                         ______________________________________                                        derivatives having the formula                                                 ##STR6##                                                                     Compound  R.sub.2       Rf*    Formula                                        ______________________________________                                        4         pentyl        0.73   C.sub.15 H.sub.30 N.sub.2 O.sub.3              5         3-methoxypropyl                                                                             0.58   C.sub.14 H.sub.28 N.sub.2 O.sub.4              6         2-ethoxyethyl 0.62   C.sub.14 H.sub.28 N.sub.2 O.sub.4              ______________________________________                                         *eluents: nButanol-Acetic acid  H.sub.2 O: 5/2/2V/V                      

                                      TABLE 3                                     __________________________________________________________________________    (R Series) derivatives having the formula                                      ##STR7##                                                                                              Melting point                                                                        Solvents of                                                                              Rf Yield                                                                             Rotary                      Compound                                                                            R.sub.1   R.sub.2  (°C.)                                                                         crystallisation                                                                          (*)                                                                              (* *)                                                                             power                                                                              Formula                __________________________________________________________________________    7     2-naphthyl                                                                              pentyl   83-86  water/alcohol (2:1)                                                                      0.84                                                                             68.8                                                                              +11.0                                                                              C.sub.26 H.sub.36                                                             N.sub.2 O.sub.4         8    3,4-dichlorophenyl                                                                      pentyl   111-4  isopropyl ether                                                                          0.87                                                                             63.8                                                                              +17.0                                                                              C.sub.22 H.sub.32                                                             Cl.sub.2 N.sub.2                                                              O.sub.4                 9    3,4-dimethylphenyl                                                                      pentyl   79-31  isopropyl ether                                                                          0.82                                                                             50.7                                                                              +15.6                                                                              C.sub.24 H.sub.38                                                             N.sub.2 O.sub.4        10    2-naphthyl                                                                              3-methoxypropyl                                                                        57-60  water/alcohol (2:1)                                                                      0.66                                                                             52.6                                                                              +6.2 C.sub.25 H.sub.34                                                             N.sub.2 O.sub.5        11    3,4-dichlorophenyl                                                                      3-methoxypropyl                                                                         97-100                                                                              water/alcohol (2:1)                                                                      0.78                                                                             47.7                                                                              +9.5 C.sub.21 H.sub.30                                                             Cl.sub.2 N.sub.2                                                              O.sub.5                12    2-naphthyl                                                                              2-ethoxyethyl                                                                          68-72  water/alcohol (2:1)                                                                      0.68                                                                             48.5                                                                              +6.0 C.sub.25 H.sub.34                                                             N.sub.2 O.sub.5        __________________________________________________________________________     (*) eluents: isoamyl alcohol/acetone/water: 5/2/1V/V                          (* *) Calculated yield starting from the gammabenzyl ester of                 Ncarbobenzoxy-D-glutamic acid                                            

                                      TABLE 4                                     __________________________________________________________________________    (S Series) derivatives having the formula                                      ##STR8##                                                                                              Melting point                                                                        Solvents of    Rotary Power                   Compound                                                                            R.sub.1   R.sub.2  (°C.)                                                                         crystallisation                                                                         Rf (*)                                                                             [alpha]D.sup.20                                                                       Formula                __________________________________________________________________________    13    2-naphthyl                                                                              pentyl   70-73  water/alcohol (2:1)                                                                     0.84 -11.0   C.sub.26 H.sub.36                                                             N.sub.2 O.sub.4        14    3,4-dichlorophenyl                                                                      pentyl   88-90  isopropyl ether                                                                         0.86 -16.6   C.sub.22 H.sub.32                                                             Cl.sub.2 N.sub.2                                                              O.sub.4                15    3,4-dimethylphenyl                                                                      pentyl   75-7   isopropyl ether                                                                         0.81 -15.2   C.sub.24 H.sub.38                                                             N.sub.2 O.sub.4        16    2-naphthyl                                                                              3-methoxypropyl                                                                        51-3   water/alcohol (2:1)                                                                     0.65 -6.0    C.sub.25 H.sub.34                                                             N.sub.2 O.sub.5        __________________________________________________________________________     (*) eluents: isoamyl alcohol/acetone/water: 5/2/1V/V                     

The powerful anti-cholecystokinin activity of the compounds which arethe subject of the invention will now be documented by a series ofpharmacological experiments conducted both in vitro and in vivo.

Studies on binding to cell membranes of ox gallbladders

The capacity of some of the compounds of the invention and of some ofthe corresponding (S series) enantiomers to inhibit the binding of[125-I]-Bolton Hunter-CCK-8 to the cholecystokinin receptors of oxgallbladder membranes was evaluated by comparison with the displacementinduced by cold (unmarked) CCK.

The ox gallbladder cell membranes were homogenised with Tris buffer (pH7.4) and the homogenate was centrifuged at 50,000 gravity for 10minutes. The membranes were then incubated with a radioactive tracer andthe compounds under study for 2 h at 25° C.

After the supernatant liquid had been discarded, the radioactivityassociated with the pellet was determined with a liquid scintillator.The specific binding was determined as the difference between thebinding in the absence and in the presence of 10⁻⁶ M CCK-8.

The results thus obtained are given in Table 5, in which the IC50 isshown, that is the concentration (in moles/liter) of the antagonist ableto displace 50% of the [125-I]-CCK-8 from the receptors.

                  TABLE 5                                                         ______________________________________                                        Inhibition of the binding of (.sup.125 I)-(B-H)-CCD-8                         Compounds IC50        Compounds   IC50                                        (R Series)                                                                              (moles/liter)                                                                             (S Series)  (moles/liter)                               ______________________________________                                        CCK-8     0.2 × 10.sup.-9                                                                     Compound 13 6.1 × 10.sup.-8                       Compound 7                                                                              1.0 × 10.sup.-9                                                                     Compound 14 4.5 × 10.sup.-7                       Compound 8                                                                              7.5 × 10.sup.-9                                                                     Compound 15 2.2 × 10.sup.-6                       Compound 9                                                                              4.4 × 10.sup.-8                                                                     Compound 16 5.6 × 10.sup.-7                       Compound 10                                                                             6.2 × 10.sup.-9                                               Compound 11                                                                             3.0 × 10.sup.-8                                               Compound 12                                                                             9.3 × 10.sup.-9                                               ______________________________________                                    

From the data given in the table it can be seen that the claimedcompounds antagonise 50% of the binding of CCK at a concentration which,for the most active compound of the R series, is only 5 times greaterthan that of the specific antagonist, thus showing a very highspecificity of action. The corresponding S-series enantiomers are onaverage 50-90 times less active.

In order to confirm what was shown by this in vitro study, some of thecompounds were also tested in vivo.

Antispastic activity on the gallbladder in mice

The emptying of the gallbladder was induced by a single oraladministration of 1 ml of a 30% suspension (weight/volume) oflyophilised egg yolk in a physiological solution.

Once it has been absorbed, the egg yolk, as stated above, induces therelease of endogenous CCK. This dose was selected as it causespractically complete emptying of the gallbladder.

The antagonist compounds were administered intraperitoneally (i.p.) 15minutes before the contractant.

The % antispastic activity for each dose was calculated by the followingformula: ##EQU1## where P₁ =average weight of the gallbladders of thegroup of animals treated with the drug plus the contractant

P₂ =average weight of the gallbladders of the group of animals treatedwith contractant only

P₃ =average weight of the gallbladders of the control group of animals.

The compounds were tested in various doses so as to enable thecalculation of the ID50 value, that is the dose (in mg/kg i.p.) which isable to inhibit the contractant effect of the egg yolk by 50%.

The results thus obtained are given in Table 6, where the effectsobtained are expressed as the ID50.

                  TABLE 6                                                         ______________________________________                                        Antispastic activity on gallbladder contraction                               induced by egg yolk.                                                                     Doses   % inhibition of the                                                                         ID50 (1)                                                (mg/kg  emptying of the                                                                             (mg/kg                                       Compound   i.p.)   gallbladder   i.p.)                                        ______________________________________                                        7 (R Series)                                                                             0.025   24.0          0.05                                                    0.05    44.2                                                                  0.1     74.0          (0.99)                                       8 (R-Series)                                                                             0.1     25.2          0.25                                                    0.03    53.2                                                                  0.1     86.3          (0.99)                                       13 (S-Series)                                                                            1       18.8          3.2                                                     3       47.7                                                                  9       80.2          (0.99)                                       ATROPINE   5       3.7                                                                   10      21.6          INACTIVE                                                15      10.5                                                       PAPAVERINE 25      0                                                                     50      0             INACTIVE                                                75      26.1                                                       ______________________________________                                         (1) r = the coefficient of correlation of the straight line of regression     The emptying of the gallbladder is reduced in a dosedependent manner by       the compounds which are the subject of the invention. Compound 7, at a        dose of 0.1 mg/kg, blocks the contraction induced by the egg yolk by          approximately 75%. Its (S) enantiomer is also active but with an ID50         value approximately 60 times larger. Atropine, on the other hand is           inactive and papeverine is slightly active, but only at the toxic dose of     75 mg/kg, which causes the death of 20% of the animals treated.          

Antispastic activity on piloric contraction in rats

This experiment shows the contractant effect of CCK on the piloricsphincter. A dose of 8 mcg/kg i.p. of CCK was used, which induces asub-maximal contraction of the pilorus.

The antagonistic compounds were administered (i.p.) 15 minutes beforethe contractant. 10 minutes after the administration of the contractant,the animals were treated per os with 25 ml/kg of H₂ O. 5 minutes afterthis administration, the animals were killed, their stomachs removed andthe gastric content measured by removal with a syringe.

The % antispactic activity for each dose administered was calculatedfrom the following formula: ##EQU2## where V₁ =the gastric-contentvolume of the group of animals treated with the drug plus thecontractant

V₂ =the gastric-content volume of the group of animals treated with thecontractant only

V₃ =the gastric-content volume of the control group of animals.

The compounds were tested at various doses so as to enable thecalculation of the ID50 value, that is the dose (in mg/kg i.p.) which isable to inhibit the contractant effect of CCK by 50%.

The results obtained are given in Table 7, where the effects obtainedare expressed as the ID50.

                  TABLE 7                                                         ______________________________________                                        Antispastic activity on piloric contraction                                   induced by CCK in the rat.                                                                Doses    % inhibition of                                                                            ID50 .sup.(1)                                           (mg/kg   piloric      (mg/kg                                      Compound    i.p.)    contraction  i.p.)                                       ______________________________________                                        7 (R Series)                                                                              0.01     27.7                                                                 0.03     48.8         0.03                                                    0.1      80.8         (0.99)                                      8 (R Series)                                                                              0.03     29.8                                                                 0.1      48.0         0.11                                                    0.3      68.1         (0.99)                                      13 (S-Series)                                                                             1        17.7         4.55                                                    3        39.0                                                                 5        54.2         (0.99)                                      ______________________________________                                         .sup.(1) : in brackets r = the coefficient of correlation of the straight     line of regression.                                                      

The piloric contraction caused by 8 mcg/kg of CCK-8 is inhibited by 50%by some of the compounds of the invention at very low doses, 30 mcg/kgin the case of compound 7, that is at a dose only 3-4 times greater thanthat of the hormonal contractant. Compound 13, on the other hand, whichis the S enantiomer of compound 7, is active only at doses approximately150 times higher.

Pancreatitis induced by sodium taurocholate

The method described by Aho et al. (Scandinavian J. Gastroenterology 15(1980), 411-16) was followed

Male rats weighing approximately 250 g were subjected to laparatomy andthe pancreas exposed. 0.3 ml of a 6% solution of sodium taurocholate wasinjected directly into the pancreatic tissue.

The products under test were administered intraperitoneally (i.p.) 30minutes before the operation and 3 hours after the operation. 6 hoursafter the laparotomy and after anaesthesia with ether, blood was removedfrom the retro-orbital plexus, the animals were killed and the pancreasremoved and weighed. The activity of the serum amylase was determined bythe Ceska method (Clin. Chim. Acta 26 (1969), 437-444).

The compounds were tested at different doses so as to enable thecalculation of the ID50 value, that is the dose (in mg/kg i.p.) which isable to inhibit the toxic effect of the sodium taurocholate by 50%,expressed both as a % inhibition of the increase in weight of thepancreas and as a % inhibition of the increase in serum amylase. Theresults obtained with compounds 7 and 8 are given in Table 8.

                  TABLE 8                                                         ______________________________________                                        Examples of proteolytic activity of the                                       claimed compounds in experimental                                             pancreatitis induced by taurocholate in rats                                                                      % Inhibi-                                                 % Inhibi-           tion in-                                          % ratio tion of             crease in                                         pancreas                                                                              weight    Amylase   amylase                                           weight  increase  in the    (ID50/                                            animal  (ID50     serum     mg/kg                                             weight  mg/kg ip) (U/ml)    ip)                                       ______________________________________                                        Controls  0.40      --        8.3     --                                      Controls +                                                                              0.51      --        14.7    --                                      Taurocholate                                                                  Compound 7                                                                    (0.3 mg/kg) +                                                                           0.47      36.4      12.0    42.2                                    Taurocholate                                                                  Compound 7                                                                    (1 mg/kg) +                                                                             0.45      54.5      9.6     79.7                                    Taurocholate                                                                  Compound 7                                                                    (3 mg/kg) +                                                                             0.41      90.8      9.0     89.0                                    Taurocholate                                                                            ID50 = 0.6                                                                              (r = 0.98)                                                                              ID50-0.4                                                                              (r =                                                                          0.94)                                   Controls  0.37      --        7. 9    --                                      Controls +                                                                              0.54      --        16.0    --                                      Taurocholate                                                                  Compound 8                                                                    (1.0 mg/kg) +                                                                           0.48      35.3      12.7    40.7                                    Taurocholate                                                                  Compound 8                                                                    (5 mg/kg) +                                                                             0.45      52.5      9.8     76.5                                    Taurocholate                                                                  Compound 8                                                                    (5 mg/kg) +                                                                             0.40      82.3      9.0     86.4                                    Taurocholate                                                                            ID50 = 1.8                                                                              (r = 0.97)                                                                              ID50 = 1.2                                                                            (r =                                                                          0.97)                                   ______________________________________                                         (r) = correlation coefficient                                            

Sodium taurocholate induces pancreatitis which causes an increase inweight of the organ which also becomes oedematous, lacking in elasticityand haemorrhagic.

Moreover, the serum amylase almost doubles. These effects are blocked ina dose-dependent manner by the compounds which are the subject of theinvention. For example, a dose of approximately 0.5 mg/kg i.p. of thecompound 7 inhibits the increase in weight of the pancreas and theincrease in serum amylase by 50%.

The experimental data given above have thus shown the possible utilityof these compounds in the treatment of various pathalogical conditionsaffecting the gastrointestinal tract, for example in spastic syndromesand pain generally, such as biliary diskinesia, or for encouragingemptying of the stomach and thus encouraging digestion.

These products could be used to particular advantage for the treatmentof pancreatitis since safely active drugs whose efficacy has been shownby pertinent pharmacological experiments are lacking for thispathological condition. A favourable therapeutic use can also beenvisaged for many of the subject compounds in the treatment of variousforms of anorexia and also in the treatment of some pathologicalconditions of the CNS linked to deficiencies in the physiological neuronlevels of CCK or other bioactive peptides.

We claim:
 1. Pharmaceutically active derivatives of (R)5-pentylamino-5-oxopentanoic acid having the formula: ##STR9## in whichR₁ is 3,4-dichlorophenyl and R₂ is selected from the group consisting ofpentyl group and 3-methoxypropyl group in which the substituents on thecentral chiral group (marked with an asterisk in formula (I)) have the R(rectus) conformation, and pharmaceutically-acceptable salts thereof. 2.A pharmaceutical preparation including, as the active constituent, ananti-cholecystokinin effective amount of a compound selected frompharmaceutically active derivatives of (R) 5-pentylamino-5-oxopentanoicacid having the formula: ##STR10## in which R₁ is 3,4-dichlorophenyl andR₂ is selected from the group consisting of the pentyl group and the3-methoxypropyl group in which the substituents on the central chiralgroup (marked with an asterisk in formula (I)) have the R (rectus)conformation, and pharmaceutically-acceptable salts thereof.
 3. Apharmaceutical preparation as in claim 2, further includingpharmaceutically-acceptable inactive ingredients selected from the groupconsisting of excipients, binders, flavourings, dispersants,preservatives, humectants and mixtures thereof.
 4. A process fortreating a patient having a spastic condition which comprisesadministering an anti-spastic effective amount of a compound of theformula (I) of claim 1 or pharmaceutically acceptable salt thereof.
 5. Aprocess for treating a patient having pancreatitis which comprisesadministering to the patient an amount of a compound of the formula (I)of claim 1 or pharmaceutically acceptable salt thereof, effect in thetreatment of pancreatitis.
 6. A process for treating a patient having apathological condition of the CNS linked to deficiencies in thephysiologically neuron levels of cholecystokinin or other bioactivepolypeptide related thereto, which comprises administering to the patentan anti-cholecystokinin or other bioactive polypeptide related theretoeffective amount of a compound of formula (I) of claim 1 or apharmaceutically acceptable salt thereof.
 7. The pharmaceuticalpreparation of claim 2, wherein R₁ is 3,4-dichlorophenyl and R₂ ismethoxypropyl.
 8. The process of claim 4, wherein in the compound of theformula (I) R₁ is 3,4-dicholorophenyl and R₂ is 3 methoxypropyl.
 9. Theprocess of claim 5, wherein in the compound of the formula (I) R₁ is3,4-dicholorophenyl and R₂ is 3-methoxypropyl.
 10. The process of claim6, wherein in the compound of the formula (I) R₁ is 3,4-dicholorophenyland R₂ is 3-methoxypropyl.
 11. A derivative according to claim 1,wherein R₂ is the pentyl group.
 12. A derivative according to claim 1,wherein R₂ is the 3-methoxypropyl group.
 13. The pharmaceuticalpreparation of claim 2 wherein R₂ is the pentyl group.
 14. The processof claim 4, wherein in the compound of the Formula (I) R₂ is the pentylgroup.
 15. The process of claim 5, wherein in the compound of theFormula (I) R₂ is the pentyl group.
 16. The process of claim 6, whereinin the compound of the Formula (I) R₂ is the pentyl group.